Method for decreasing QT dispersion or inhibiting the progression of QT dispersion with an angiotensin II receptor antagonist

Abstract

Angiotensin II receptor antagonists are useful for decreasing QT dispersion or inhibiting the progression of QT prolongation in patients. Also disclosed is a method for monitoring the reduction in die risk of experiencing an adverse cardiac event, such as sudden cardiac death, myocardial infarction or arrhythmias, using QT dispersion in patients treated with a therapeutically effective amount of an angiotensin II antagonist.

What is claimed is:  
     
       1. A method for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist. 
     
     
       2. The method, as recited in claim  1  for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist wherein the angiotensin II receptor antagonist comprises: candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, 3-(2′-(tetrazol-5-yl)-1,1′-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine, 4′[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]-benzimidazol-1-yl]-methyl]-1,1′-biphenyl]-2-carboxylic acid, 2-butyl-6-(1-methoxy-1-methylethyl)-2-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]guinazolin-4(3H)-one, 3-[(2′-carboxybiphenyl-4-yl)methyl]-2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine, 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-carboxylic acid, 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid-1-(ethoxycarbonyl-oxy)ethyl ester potassium salt, 720,] dipotassium 2-butyl-4-(methylthio)-1-[[2-[[[(propylamino)carbonyl]amino]-sulfonyl](1,1′-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate, methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophencarboxylate, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine, 6-butyl-2-(2-phenylethyl)-5-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-methyl]pyrimidin-4-(3H)-one D,L lysine salt, 5-methyl-7-n-propyl-8-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-[1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, 2,7-diethyl-5-[[2′-(5-tetrazolyl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole potassium salt, 2-[2-butyl-4,5-dihydro-4-oxo-3-[2′-(1H-tetrazol-5-yl)-4-biphenylmethyl]-3H-imidazol[4,5-c]pyridine-5-ylmethyl]-benzoic acid, ethyl ester, potassium salt, 3-methoxy-2,6-dimethyl-4-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methoxy]pyridine, 2-ethoxy-1-[[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, 1-[N-(2′-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl)-N-valerolylaminomethyl)cyclopentane-1-carboxylic acid, 7-methyl-2n-propyl-3-[[2′1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-6]pyridine, 2-[5-[(2-ethyl-5,7-dimethyi-3H-imidazo[4,5-b]pyridine-3-yl)methyl]-2-quinolinyl]sodium benzoate, 2-butyl-6-chloro-4-hydroxymethyl-5-methyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyridine, 2-[[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methyl]amino]benzoic acid tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-6-one, 4(S)-[4-(carboxymethyl)phenoxy]-N-[2(R)-[4-(2-sulfobenzamido)imidazol-1-yl]octanoyl]-L-proline, 1-(2,6-dimethylphenyl)-4-butyl-1,3-dihydro-3-[[6-[2-(1H-tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one, 5,8-ethano-5,8-dimethyl-2-n-propyl-5,6,7,8-tetrahydro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H,4H-1,3,4a,8a-tetrazacyclopentanaphthalene-9-one, 4-[1-[2′-(1,2,3,4-tetrazol-5-yl)biphen-4-yl)methylamino]-5,6,7,8-tetrahydro-2-trifylquinazoline, 2-2-chlorobenzoyl)imino-5-ethyl-3-[2′-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl-1,3,4-thiadiazoline, 2-[5-ethyl-3-[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-1,3,4-thiazoline-2-ylidene]aminocarbonyl-1-cyclopentencarboxylic acid dipotassium salt, or 2-butyl-4-[N-methyl-N-(3-methylcrotonoyl)amino]-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid 1-ethoxycarbonyloxyethyl ester. 
     
     
       3. The method, as recited in claim  2 , wherein the angiotensin II receptor antagonist is selected from the group consisting of: candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-carboxylic acid, and 3-(2′-(tetrazol-5-yl )-1,1′-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine. 
     
     
       4. A method, as recited in claim  1 , for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist of formula I                    
       wherein: 
       R 1  is:                    
       R 2  is H; Cl; Br; I; F; NO 2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO 2 H; CO 2 R 9 ; HNSO 2 CH 3 ; NHSO 2 CF 3 ; CONHOR 12 ; SO 2 NH 2 ;                    
        aryl; or furyl;  
       R 3  is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;  
       R 4  is CN, NO 2  or CO 2 R 11 ;  
       R 5  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;  
       R 6  is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO 2 R 14 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl 5 to 10 carbon atoms; (CH 2 ) s Z(CH 2 ) m R 5  optionally substituted with F or CO 2 R 14 ; benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;  
       R 7  is H, F, Cl, Br, I, NO 2 , C v F 2v+1 , where v=1-6, C 6 F 5 ; CN;                    
        straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH 3 , CF 3 , and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl;  
       R 8  is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; —(CH 2 ) m -imidazol-1-yl; —(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two group selected from CO 2 CH 3  or alkyl of 1 to 4 carbon atoms; —(CH 2 ) s  tetrazolyl;                    
       R 10  is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH 2 ) p C 6 H 5 ;  
       R 11  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;  
       R 12  is H, methyl or benzyl;                    
       R 14  is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;  
       R 15  is H, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;  
       R 16  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) p C 6 H 5 , OR 17 , or NR 18 R 19 ;  
       R 17  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;  
       R 18  and R 19  independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, α-methylbenzyl, or taken together with the nitrogen form a ring of the formula                    
       Q is NR 20 , O or CH 2 ;  
       R 20  is H, alkyl of 1-4 carbon atoms, or phenyl;  
       R 21  is alkyl of 1 to 6 carbon atoms, —NR 22 R 23 , or                    
       R 22  and R 23  ndependently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH 2 ) u , where u is 3-6;  
       R 24  is H, CH 3  or —C 6 H 5 ;  
       R 25  is NR 27 R 28 , OR 28 , NHCONH 2 , NHCSNH 2 ,                    
       R 26  is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or alkyl;  
       R 27  and R 28  are independently hydrogen, alkyl with from 1 to carbon atoms, or phenyl;  
       R 29  and R 30  are independently alkyl of 1-4 carbon atoms or taken together are —(CH 2 ) q —;  
       R 31  is H, alkyl or 1 to 4 carbon atoms, or —CH 2 CH═CH 2 ;  
       X is a carbon-carbon single bond, —CO—, —CH 2 —, —O—, —S—, —NH—,                    
        —OCH 2 —, —CH 2 O—, —SCH 2 —, —CH 2 S—, —NHC(R 27 )(R 28 )—, —NR 23 SO 2 —, —SO 2 NR 23 —, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH 2 CH 2 —, —C(R 27 )(R 28 )NH—, —CF 2 CF 2 —;                    
       Y is O or S;  
       Z is O, NR 11 , or S;  
       m is 1 to 5;  
       n is 1 to 10;  
       p is 0 to 3;  
       q is 2 to 3;  
       r is 0 to 2;  
       s is 0 to 5;  
       t is 0 or 1;  
       or pharmaceutically acceptable salts of these compounds; provided that: 
       (1) the R 1  group is not in the ortho position;  
       (2) when R 1  is                    
       X is a single bond, and R 13  is CO 2 H, or                    
       then R 13  must be in the ortho or meta position; or when R 1  and X are as above and R 13  is NHSO 2 CF 3  or NHSO 2 CH 3 , R 13  must be ortho;  
       (3) when R 1  is                    
       and X is other than a single bond, then R 13  must be ortho except when X═NR 23 CO and R 13  is NHSO 2 CF 3  or NHSO 2 CH 3 , then R 13  must be ortho or meta;  
       (4) when R 1  is 4-CO 2 H or a salt thereof, R 6  cannot be S-alkyl;  
       (5) when R 1  is 4-CO 2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH 2 OH, CH 2 OCOCH 3 , or CH 2 CO 2 H;  
       (6) when R 1  is                    
       X is —OCH 2 —, and R 13  is 2-CO 2 H, and R 7  is H then R 6  is not C 2 H 5 S;  
       (7) when R 1  is                    
        and R 6  is n-hexyl then R 7  and R 8  are not both hydrogen;  
       (8) when R 1  is                    
        R 6  is not methoxybenzyl;  
       (9) the R 6  group is not                    
       (10) when r=0, R 1  is                    
       X is                    
        R 13  is 2-NHSO 2 CF 3 , and R 6  is n-propyl, then R 7  and R 8  are not —CO 2 CH 3 ;  
       (11) when r=0, R 1  is                    
       X is                    
        R 13  is 2-COOH, and R 6  is n-propyl, then R 7  and R 8  are not —CO 2 CH 3 ;  
       (12) when r=1,                    
       X is a single bond, R 7  is Cl, and R 8  is —CHO, then R 13  is not 3-(tetrazol-5-yl);  
       (13) when r=1,                    
       X is a single bond, R 7  is Cl, and R 8  is —CHO, then R 13  is not 4-(tetrazol-5-yl).  
     
     
       5. The method, as recited in claim  4 , for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist of formula I:                    
       wherein: 
       R 1  is —CO 2 H; —NHSO 2 CF 3 ;                    
       R 6  is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, or nitro;  
       R 8  is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, —(CH 2 ) m -imidazol-1yl, —(CH 2 ) m 1,2,3-triazolyl optionally substituted with one or two groups selected from CO 2 CH 3  or alkyl of 1 to 4 carbon atoms,                    
       R 16  is H, alkyl of 1 to 5 carbon atoms, OR 17 , or NR 18 R 19 ;  
       X is carbon-carbon single bond, —CO—,                    
        —OCH 2 —, —CH 2 O—, —SCH 2 —, —CH 2 S—, —NHCH 2 —, —CH 2 NH— or —CH═CH—; or pharmaceutically acceptable salts of these compounds.  
     
     
       6. The method, as recited in claim  5 , for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist of formula I, wherein 
       R 2  is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;  
       R 6  is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;                    
       R 10  is CF 3 , alkyl of 1 to 6 carbon atoms or phenyl;  
       R 11  is H, or alkyl of 1 to 4 carbon atoms;  
       R 13  is CO 2 H; CO 2 CH 2 OCOC(CH 3 ) 3 ; NHSO 2 CF 3 ;                    
       R 14  is H, or alkyl of 1 to 4 carbon atoms;  
       R 15  is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;  
       R 16  is H, alkyl of 1 to 5 carbon atoms; OR 17 ; or                    
       m is 1 to 5;  
       X is single bond, —O—; —CO—; —NHCO—; or —OCH 2 —;  
       or pharmaceutically acceptable salts thereof. 
     
     
       7. The method, as recited in claim  6 , for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist of formula I which is selected from the group consisting of: 
       2-Butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole;  
       2-Butyl-4-chloro-1-[(2′-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole;  
       2-Butyl-4-chloro-1-[(2′-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)aminomethyl]imidazole;  
       2-Butyl-4-chloro-1-[(2′-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)aminomethyl]imidazole;  
       2-Butyl-4-chloro-1-[(2′-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde;  
       2-Butyl-1-[(2′-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;  
       2-(1E-Butenyl)-4-chloro-1-[(2′-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole;  
       2-(1E-Butenyl)-4-chloro-1-[(2′-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;  
       2-Propyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole;  
       2-Propyl-4-chloro-1[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;  
       2-Butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidzole-5-carboxaldehyde;  
       2-(1E-Butenyl)-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole;  
       2(1E-Butenyl)-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde;  
       2-Butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid;  
       2-Propyl-4-chloro-1-[(2-′(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid;  
       2-Propyl-4-trifluoromethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid;  
       2-Propyl-4-trifluoromethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxylmethyl)imidazole;  
       2-Butyl-4-trifluoromethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid;  
       2-Propyl-4-trifluoromethyl-1-[(2′-(carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;  
       2-Propyl-4-pentafluoroethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole;  
       2-Propyl-1-[(2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-4,5,-dicarboxylic acid;  
       2-Propyl-4-pentafluoroethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid;  
       2-Propyl-4-pentafluoroethyl-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde,  
       and its pharmaceutically acceptable salts thereof. 
     
     
       8. The method, as recited in claim  7 , for decreasing QT dispersion or inhibiting the progression of QT dispersion by administering to a patient in need of such treatment a therapeutically effective amount of an angiotensin II receptor antagonist selected from: 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(hydroxymethyl)imidazole; or 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl]methylimidazole-5-carboxylic acid or its pharmaceutically acceptable salt thereof. 
     
     
       9. The method, as recited in claim  8 , wherein the patient is a symptomatic heart failure patient. 
     
     
       10. A method for monitoring the reduction in risk of experiencing an adverse cardiac event comprising monitoring QT dispersion in patients treated with a therapeutically effective amount of an angiotensin II receptor antagonist. 
     
     
       11. The method, as recited in claim  10 , for monitoring the reduction in risk of experiencing an adverse cardiac event comprising monitoring QT dispersion in patients treated with a therapeutically effective amount of an angiotensin II receptor comprising: candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, 3-(2′-(tetrazol-5-yl)-1,1′-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine, 4′[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]-benzimidazol-1-yl]-methyl]-1,1′-biphenyl]-2-carboxylic acid, 2-butyl-6-(1-methoxy-1-methylethyl)-2-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]guinazolin-4(3H)-one, 3-[(2′-carboxybiphenyl-4-yl)methyl]-2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine, 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-carboxylic acid, 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid-1-(ethoxycarbonyl-oxy)ethyl ester potassium salt, dipotassium 2-butyl-4-(methylthio)-1-[[2-[[[(propylamino)carbonyl]amino]-sulfonyl](1,1′-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate, methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophencarboxylate, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine, 6-butyl-2-(2-phenylethyl)-5-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-methyl]pyrimidin-4-(3H)-one D,L lysine salt, 5-methyl-7-n-propyl-8-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-[1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, 2,7-diethyl-5-[[2′-(5-tetrazolyl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole potassium salt, 2-[2-butyl-4,5-dihydro-4-oxo-3-[2′-(1H-tetrazol-5-yl)-4-biphenylmethyl]-3H-imidazol]4,5-c]pyridine-5-ylmethyl]-benzoic acid, ethyl ester, potassium salt, 3-methoxy-2,6-dimethyl-4-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methoxy]pyridine, 2-ethoxy-1-[[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, 1-[N-(2′-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl)-N-valerolylaminomethyl)cyclopentane-1-carboxylic acid, 7-methyl-2n-propyl-3-[[2′1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-6]pyridine, 2-[5-[(2-ethyl-5,7-dimethyl-3H-imidazo4,5-b]pyridine-3-yl)methyl]-2-quinolinyl]sodium benzoate, 2-butyl-6-chloro-4-hydroxymethyl-5-methyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyridine, 2-[[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methyl]amino]benzoic acid tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-6-one, 4(S)-[4-(carboxymethyl)phenoxy[-N-[2(R)-[4-(2-sulfobenzamido)imidazol-1-yl]octanoyl]-L-proline, 1-(2,6-dimethylphenyl)-4-butyl-1,3-dihydro-3-[[6-[2-(1H-tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one, 5,8-ethano-5,8-dimethyl-2-n-propyl-5,6,7,8-tetrahydro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H,4H-1,3,4a,8a-tetrazacyclopentanaphthalene-9-one, 4-[1-2′-(1,2,3,4-tetrazol-5-yl)biphen-4-yl)methylamino]-5,6,7,8-tetrahydro-2-trifylquinazoline, 2-(2-chlorobenzoyl)imino-5-ethyl-3-[2′-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl-1,3,4-thiadiazoline, 2-[5-ethyl-3-[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-1,3,4-thiazoline-2-ylidene]aminocarbonyl-1-cyclopentencarboxylic acid dipotassium salt, and 2-butyl-4-[N-methyl-N-(3-methylcrotonoyl)amino]-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid 1-ethoxycarbonyloxyethyl ester. 
     
     
       12. The method, as recited in claim  10 , wherein the adverse cardiac event comprises: sudden cardiac death, myocardial infarction or arrhythmias. 
     
     
       13. The method, as recited in claim  12 , wherein the angiotensin II receptor antagonist comprises: candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-carboxylic acid, or 3-(2′-(tetrazol-5-yl)-1,1′-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine. 
     
     
       14. A method for monitoring the reduction in the risk of experiencing an adverse cardiac event comprising monitoring QT dispersion in patients treated with a therapeutically effective amount of an angiotensin II receptor antagonist, wherein the angiotensin II receptor antagonist of formula I                    
       wherein: 
       R 1  is:                    
       R 2  is H; Cl; Br; I; F; NO 2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO 2 H; CO 2 R 9 ; HNSO 2 CH 3 ; NHSO 2 CF 3 ; CONHOR 12 ; SO 2 NH 2 ;                    
        aryl; or furyl;  
       R 3  is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;  
       R 4  is CN, NO 2  or CO 2 R 11 ;  
       R 5  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;  
       R 6  is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO 2 R 14 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl 5 to 10 carbon atoms; (CH 2 ) s Z(CH 2 ) m R 5  optionally substituted with F or CO 2 R 14 ; benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;  
       R 7  is H, F, Cl, Br, I, NO 2 , C v F 2v+1 , where v=1-6, C 6 F 5 ; CN;                    
        straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH 3 , CF 3 , and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl;  
       R 8  is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; —(CH 2 ) m -imidazol-1-yl; —(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two group selected from CO 2 CH 3  or alkyl of 1 to 4 carbon atoms; —(CH 2 ) s  tetrazolyl;                    
       R 10  is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH 2 ) p C 6 H 5 ;  
       R 11  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;  
       R 12  is H, methyl or benzyl;  
       R13 is —CO 2 H; —CO 2 R 9 ; —CH 2 CO 2 H, —CH 2 CO 2 R 9 ;                    
       R 14  is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;  
       R 15  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, or phenacyl;  
       R 16  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) p C 6 H 5 , OR 17 , or NR 18 R 19 ;  
       R 17  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;  
       R 18  and R 19  independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, α-methylbenzyl, or taken together with the nitrogen form a ring of the formula                    
       Q is NR 20 , O or CH 2 ;  
       R 20  is H, alkyl of 1-4 carbon atoms, or phenyl;  
       R 21  is alkyl of 1 to 6 carbon atoms, —NR 22 R 23 , or                    
       R 22  and R 23  independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH 2 ) u , where u is 3-6;  
       R 24  is H, CH 3  or —C 6 H 5 ;  
       R 25  is NR 27 R 28 , OR 28 , NHCONH 2 , NHCSNH 2 ,                    
       R 26  is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;  
       R 27  and R 28  are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;  
       R 29  and R 30  are independently alkyl of 1-4 carbon atoms or taken together are —(CH 2 ) q —;  
       R 31  is H, alkyl or 1 to 4 carbon atoms, or —CH 2 CH═CH 2 ;  
       X is a carbon-carbon single bond, —CO—, —CH 2 —, —O—, —S—, —NH—,                    
        —NHC(R 27 )(R 28 )—, —NR 23 SO 2 —, —SO 2 NR 23 —, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH 2 CH 2 —, —C(R 27 )(R 28 )NH—, —CF 2 CF 2 —;                    
       Y is O or S;  
       Z is O, NR 11 , or S;  
       m is 1 to 5;  
       n is 1 to 10;  
       p is 0 to 3;  
       q is 2 to 3;  
       r is 0 to 2;  
       s is 0 to 5;  
       t is 0 or 1;  
       or pharmaceutically acceptable salts of these compounds; provided that: 
       (1) the R 1  group is not in the ortho position;  
       (2) when R 1  is                    
       X is a single bond, and R 13  is CO 2 H, or                    
       then R 13  must be in the ortho or meta position; or when R 1  and X are as above and R 13  is NHSO 2 CF 3  or NHSO 2 CH 3 , R 13  must be ortho;  
       (3) when R 1  is                    
       and X is other than a single bond, then R 13  must be ortho except when X═NR 23 CO and R 13  is NHSO 2 CF 3  or NHSO 2 CH 3 , then R 13  must be ortho or meta;  
       (4) when R 1  is 4-CO 2 H or a salt thereof, R 6  cannot be S-alkyl;  
       (5) when R 1  is 4-CO 2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH 2 OH, CH 2 OCOCH 3 , or CH 2 CO 2 H;  
       (6) when R 1  is                    
       X is —OCH 2 —, and R 13  is 2-CO 2 H, and R 7  is H then R 6  is not C 2 H 5 S;  
       (7) when R 1  is                    
        and R 6  is n-hexyl then R 7  and R 8  are not both hydrogen;  
       (8) when R 1  is                    
        R 6  is not methoxybenzyl;  
       (9) the R 6  group is not                    
       (10) when r=0, R 1  is                    
       X is                    
        and R 6  is n-propyl, then R 7  and R 8  are not —CO 2 CH 3 ;  
       (11) when r=0, R 1  is                    
       X is                    
        R 13  is 2-COOH, and R 6  is n-propyl, then R 7  and R 8  are not —CO 2 CH 3 ;  
       (12) when r=1,                    
       X is a single bond, R 7  is Cl, and R 8  is —CHO, then R 13  is not 3-(tetrazol-5-yl);  
       (13) when r=1,                    
       X is a single bond, R 7  is Cl, and R 8  is —CHO, then R 13  is not 4-(tetrazol-5-yl).  
     
     
       15. The method, as recited in claim  14 , wherein the adverse cardiac event comprises: sudden cardiac death, myocardial infarction or arrhythmias. 
     
     
       16. The method, as recited in claim  15 , where the imidazole angiotensin II receptor antagonist of formula I is 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(hydroxymethyl)imidazole; or 2-butyl-4-chloro-1-[(2′-tetrazol-5-yl)biphenyl-4-yl]methylimidazole-5-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
       17. The method, as recited in claim  16 , wherein the patient is a symptomatic heart failure patient.